SUMMARY Influenza virus infection is a major health concern worldwide. Our best defense against seasonal influenza virus infections is vaccination, but current vaccine strategies are not fully effective and may not offer protection against viruses that emerge from animals. One impediment to the development of better vaccines is the lack of a tractable and cost-effective small animal model for testing new vaccine technology. Mice are ubiquitously used in research, but influenza viruses that infect humans often require adaptation in order to infect and cause pathology in mice. This requirement for virus adaptation limits the utility of the mouse model for testing human vaccine candidates in challenge studies with relevant non-adapated human viruses. However, we found that mice engineered to lack a critical antiviral restriction factor known as interferon-induced transmembrane protein 3 (IFITM3) show increased susceptibility to a variety of influenza virus strains, including human isolates that otherwise do not cause significant pathology in wild type mice. We propose that IFITM3 knockout mice may thus serve as a long-sought mouse model for influenza virus vaccine testing. We will test whether these mice possess the two characteristics needed in a pre-clinical testing model: 1) Whether IFITM3 knockout mice possess the ability to mount protective adaptive immune responses upon vaccination, and 2) Whether IFITM3 knockout mice are fully susceptible to a wide breadth of human and animal-derived influenza viruses. In addition to allowing more rapid and cost-effective testing of new seasonal and universal influenza virus vaccines, this research will also provide insights into humans who possess IFITM3 defects in terms of virus susceptibility and the ability to counteract this immunodeficiency with vaccination.